Dual inhibition of EGFR and mTOR pathways in small cell lung cancer.

BACKGROUND: In this report we investigated the combination of epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) pathway inhibition as a possible new therapeutic strategy for small cell lung cancer (SCLC). METHODS: EGFR, p-AKT, p-ERK, p-mTOR and p-p70s6K protein expressions were studied by immunohistochemistry in 107 small cell lung carcinomas and correlated with clinicopathological parameters. Cells of SCLC were treated with erlotinib+/-RAD001 and analysed for cell viability, proliferation, autophagy, and pathway regulation. RESULTS: Epidermal growth factor receptor, p-AKT, p-ERK, p-mTOR, and p-p70s6K were expressed in 37, 24, 13, 55 and 91% of the tumour specimens of all SCLC patients, respectively, and were not associated with disease-free or overall survival. The expression of EGFR was lower in neoadjuvant-treated patients (P=0.038); mTOR pathway activation was higher in the early stages of disease (P=0.048). Coexpression of EGFR/p-mTOR/p-p70s6K was observed in 28% of all patients . EGFR immunoreactivity was associated with p-ERK and p-mTOR expression (P=0.02 and P=0.0001); p-mTOR immunoreactivity was associated with p-p70s6K expression (P=0.001). Tumour cells comprised a functional EGFR, no activating mutations in exons 18-21, and resistance to RAD001 monotherapy. We found synergistic effects of erlotinib and RAD001 combination therapy on the molecular level, cell viability, proliferation and autophagy. CONCLUSIONS: The combined inhibition of EGFR/mTOR pathways could be a promising approach to treat SCLC.

Selective resection of colorectal liver metastases.

AIMS: Safety of liver surgery for colorectal cancer liver metastases after neoadjuvant chemotherapy has to be re-evaluated. PATIENTS AND METHODS: Two hundred Patients were prospectively analyzed after surgery for colorectal cancer liver metastases between 2001 and 2004 at our institution. Special emphasis was given to perioperative morbidity and mortality under modern perioperative care. RESULTS: There was no in-hospital mortality and the perioperative morbidity was 10% (20/200). Four patients had to be reoperated due to bile leak or intraabdominal abscess. The remainder either had infectious complications or pleural effusion and/or ascites requiring tapping. Variables strongly associated with decreased survival were T, N, G and UICC (International Union against cancer) classification of the primary, hepatic lesions>5 cm and elevated tumour markers. Short disease free interval and neoadjuvant chemotherapy without response predicted impaired recurrence free survival (RFS). Multivariate analysis revealed lymph node status and differentiation of the primary, presence of extrahepatic tumour and gender as factors associated with decreased survival. Administration of neoadjuvant chemotherapy was not associated with higher postoperative morbidity or prolonged hospital stay. CONCLUSIONS: Modern dissection techniques and improved perioperative care contributed to a very low rate of surgery-related morbidity (10%) and a zero percent mortality which was also observed in patients pretreated with neoadjuvant chemotherapy prior to resection. Liver resection in experienced hands has become a safe part in the potentially curative attempt of treating patients with metastatic colorectal cancer.

Bevacizumab protects against sinusoidal obstruction syndrome and does not increase response rate in neoadjuvant XELOX/FOLFOX therapy of colorectal cancer liver metastases.

AIM: In patients suffering from colorectal cancer liver metastases, 5-fluorouracil-based chemotherapy plus oxaliplatin ensures superior response rates at the cost of hepatic injury. Knowledge about the consequences of bevacizumab on chemotherapy-induced hepatic injury and tumor response is limited. METHODS: Resected liver specimens from patients of two prospective, non-randomized trials (5-fluorouracil/oxaliplatin+/-bevacizumab) were analyzed retrospectively. Hepatotoxicity to the non-tumor bearing liver was evaluated for sinusoidal obstruction syndrome, hepatic steatosis and fibrosis. Tumor response under chemotherapy was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST). RESULTS: Bevacizumab decreased the severity of the sinusoidal obstruction syndrome. Bevacizumab had no impact on hepatic steatosis and fibrosis. The addition of bevacizumab to chemotherapy had no effect on tumor response compared to combination chemotherapy alone. CONCLUSIONS: This analysis shows that bevacizumab protects against the sinusoidal obstruction syndrome and thus provides the histological explanation of the safe use of bevacizumab prior to liver resection. Furthermore, we show that bevacizumab does not improve tumor response according to RECIST.

[Controlled study on the possible benefits of combination therapy with chlorimipramine and haloperidol inpatients with endogenous depression]. / Kontrollierte Studie über die möglichen Vorteile einer Kombinationstherapie mit Chlorimipramin und Haloperidol bei endogen Depressiven.

Ther is some clinical evidence that neuroleptics are able to increase the therapeutic effect of antidepressive drugs. From a theoretical viewpoint this could be due to influences on pharmacokinetic or receptor sensibility. In a controlled trial on 20 endogenous depressives the advantage of a combined medication of 150 mg Chlorimipramine and 9 mg p.d. Haloperidol (given over six days) were tested. Neither during the combined medication, nor after discontinuation of haloperidol, this treatment regimen proved better clinical results. According to the literature serum levels of chlorimipramine were higher in the experimental group, not the levels of desmethyl-chlorimipramine.

Controlled trial on the possible advantages of a combined therapy with maprotiline and haloperidol in endogenous depression.

There is some clinical evidence that neuroleptics are able to increase the therapeutic effect of antidepressant drugs. From a theoretical viewpoint this could be due to influences on pharmacokinetics or receptor sensitivity. In a controlled three-week trial in 28 patients with endogenous depression the potential advantages of a combined medication of 150 mg maprotiline and 9 mg haloperidol per day (given for the first six days) in comparison with monotherapy with maprotiline were tested. Neither during the time of combined medication nor following withdrawal of haloperidol did this treatment regimen show better clinical results in comparison with controls. In keeping with results described elsewhere, the serum levels of the antidepressant, but not of its desmethyl metabolite, were higher in the experimental group.

Urinary bladder volumetry by means of a single retrosymphysically implantable ultrasound unit.

AIMS: Optimal voiding is a crucial issue for patients with neurogenic bladder dysfunctions to prevent long-term damage to the urinary tract. In prior studies, implantable ultrasound (US) sensors have proved an appropriate method of measuring the urinary bladder volume. Their disadvantage is that they tend to dislocate in chronic applications as they are fixed directly onto the bladder wall. In the present study, we describe an implantable US volumetry unit that does not require fixing to the bladder wall and consists of a single receiver-transmitter unit. MATERIALS AND METHODS: Six Göttinger minipigs were anesthetized in ITN; a sensor was stitched behind the symphysis into the periosteum and aligned to the bladder so that an US measurement could take place in ventro-dorsal direction. In steps of 50 ml, the bladder was filled up to 250 ml via a transurethral catheter; after each filling step the volume was measured three times and compared to the instilled volume. RESULTS: On average the measurements with implanted US differed from the actual bladder filling by 77.4% at a bladder filling of 50 ml ("error" messages were included as 0 ml), 3.8% at 100 ml, 3.8% at 150 ml, and 0.3% at 200 ml, and 3.6% at 250 ml. When the empty bladder (= 0 ml) was measured, the US sensor detected no volume in 73% of the cases. CONCLUSIONS: In our animal model, the above-described US system proved tantamount with other external US measuring units and presented a precise and low-artefact system, allowing reliable measuring of the urinary volume with good chances of preserving these positive qualities over time. We expect that clinical application of this system may help to determine the optimal voiding time and thus to avoid bladder over-extension and damage to the urinary tract over time.